Development of structurally extended benzosiloxaboroles - synthesis andin vitrobiological evaluation

Abstract

The synthesis of potassium 6-hydroxy-7-chloro-1,1-dimethyl-3,3-difluorobenzo-1,2,3-siloxaborolate5bfrom readily available 4-bromo-2-chlorophenol was developed. This compound proved useful in various derivatizations resulting in a wide range ofO-functionalized benzosiloxaboroles. Reactions of5bwith selected substituted benzoyl chlorides gave rise to a series of respective derivatives with 6-benzoate side groups attached to the benzosiloxaborole core. Furthermore, treatment of5bwith substituted benzenesufonyl chlorides afforded several benzosiloxaboroles bearing functionalized benzenesulfonate moieties at the 6 position. The synthesis of related chloropyridine-2-yloxy substituted benzosiloxaboroles was accomplished by a standard approach involving silylation/boronation of appropriate heterodiaryl ethers. Investigation of biological activity of obtained compounds revealed that some benzoate and most benzenesulfonate derivatives exhibit high activity against Gram-positive cocci such as methicillin-sensitiveStaphylococcus aureusATCC 6538P as well as methicillin-resistantS. aureusATCC 43300 with the MIC values in the range of 0.39-3.12 mg L−1. Some benzenesulfonate derivatives showed also potent activity againstEnterococcus faecalisATCC 29212 andE. faeciumATCC 6057 with MIC = 6.25 mg L−1. Importantly, for the most promising cocci-active benzenesulfonate derivatives the obtained MIC values were far below the cytotoxicity limit determined with respect to human normal lung fibroblasts (MRC-5). For those derivatives, the obtained IC50values were higher than 12.3 mg L−1. The results of antimicrobial activity and cytotoxicity indicate that the tested compounds can be considered as potential antibacterial agents.